1. Field of the Invention
This invention relates broadly to a new method of curing stabilized cyanoacrylate adhesives coincidently with their application to a substrate, particularly with reference to medical procedures using such adhesives and new devices for using the method.
2. Description of the Prior Art
Medical interest in cyanoacrylate polymers was apparent in the mid-nineteen sixties as evidenced by numerous reports on its use as a tissue bonding agent. Collins, et al reported on the effectiveness of homologous chain cyanoacrylates for bonding of biological substrates (1,2). They observed high rates of polymerization with longer chain esters than the methyl or ethyl monomers. There appeared to be more biocompatability with the longer chains as noted by the ease of spreading monomer films on biosubstrates. This contrasted with in vitro polymerizations where the lower homologues reacted much faster. There was particular interest in the degradation of these polymers as they related to possible harmful effects that would preclude their use in surgery. Woodward, et al (3) reported histotoxicity of these monomers in rat tissue. The study involved in situ polymerization of three cyanoacrylate monomers: methyl, hexyl, decyl. It was reported that histotoxic effects were greatest with methyl and decreased with the other two monomers.
The same group reported on the use of radioactive methyl cyanoacrylate for monitoring routes for the loss of the polymer (4, 5). Results indicated that the polymer was degraded and excreted principally through the urine and feces. Analysis of the animal's organs revealed no signs of radioactivity. This implied no degradation products were incorporated into any of the animal's metabolic pathway. By analogy to poly-vinylidene cyanide, they noted that the cyanoacrylate polymer degraded in the presence of water and more so in the presence of bases. The first observed degradation product turned out to be one of the starting materials, i.e., formaldehyde. In vitro studies have shown that the polymers degrade via hydrolytic scission in homogeneous as well as heterogeneous conditions (6). These degradation products were confirmed to be formaldehyde and the corresponding cyanoacetate. The conditions of solution degradation affected the consequent rates, namely, under neutral conditions rates decreased as the homologous series was ascended while alkaline conditions increased all rates.
The same study reported that the hydroxyl group was evident in the polymer as the initiating species. This was concluded from infrared spectral data that displayed hydroxyl group absorption at 3600 cm(−1). Further support for this is the noted suppression of the OH as water is replaced with methanol and the observed methoxy absorption at 1100 cm(−1). Preferential initiation was shown to occur with NH2 containing substances such as pyridine, cysteine, alanine, and glycine in aqueous solutions. This suggested that in vivo adhesion was more than a mechanical interlocking of the solid polymer with the tissue. This appears to be the case as it was noted that typical polymer solvents were not effective in solvating tissue-bound polymer.
From this it would appear that in vivo studies of degradation do not necessarily correspond to in vitro conditions. Part of the degradation mechanism relies on the solution of polymer for hydrolytic scission. The chemical bonding of the polymer excludes this surface from hydrolytic activity. A mechanism of degradation was proposed that suggests an action similar to unzipping in acrylics, however, the difference being that the monomer is not regenerated. The proposed mechanism necessitates the presence of the hydroxyl as well as the presence of water.
An unusual effect was reported regarding the aqueous degradation of isobutyl cyanoacrylate (7). Of the monomers tested (methyl, propyl, butyl, isobutyl, heptyl, octyl), it was the only one that degraded more rapidly than any of the unbranched homologues, with the exception of the methyl.
A second study reported that in vivo experimentation give credence to the chain scission mechanism by hydrolysis (8). When beta-(14) carbon tagged cyanoacrylate is implanted in rats, radioactive urea is isolated from urine. This suggests that tagged formaldehyde is released, converted to carbon dioxide and in turn reacts with ammonia to produce urea (9).
Rates of degradation on ethyl, butyl, and hexyl cyanoacrylates were evaluated with regards to molecular weights, concentrations, and side chain structures (10). The method employed buffered systems of pH ranges from 5.97 to 7.88. As expected, the rates increased with increasing pH. Scanning electron microscopy of the degraded polymer indicated that reaction occurs at the surfaces and not internally through diffusion. It was postulated that the greater the length of the nalkyl side chain, the more protection provided to the labile hydroxyl end of the polymer chain. This in turn would provide greater resistance to degradation of the polymer. Degradation rates do in fact correspond to chain length protection. The relative rates of degradation for hexyl, butyl, and ethyl were, respectively, 1.0, 1.36, 9.55.
The same group reported on a study whereby degradation rates were retarded by increasing the chain length of the polymer (11). Very small quantities of impurities in the monomers had a significant impact on the final outcome of the degree of polymerization. Further to this study, within the ethoxyethyl system, longer chain length enhanced the degradation resistance of the resultant polymer.
A comparative study of ethyl cyanoacrylate and polyurethane in-situ generated adhesives and coatings were reported in U.S. Pat. No. 4,057,535. The study claimed the superiority of the polyurethane structure due to high flexibility and compatibility with the treated tissues. The single comparison was made with incised tissue and consequent application between the wound edges. Inferiority of this application for the cyanoacrylate was readily evident, but true topical applications were not compared. Of eleven examples given, four were of a topical method, yet no data was presented as no application of the ethyl or any other homologue was done conjunctively for comparative efficacy. A further deficiency of this patent is the practicality of use. No indication is given for a device to properly apply the two part system and appears to indicate an at-site preparation.
Another patent, U.S. Pat. No. 5,192,536 overcomes the apparent difficulty of U.S. Pat. No. 4,057,535 by taking preformed polyurethane and dissolving in a rapidly evaporating solvent such as tetrahydrofuran. The composition is designed to form a “membrane-like cover over the wound” and “assists in maintaining closure of the wound”. Again no comparative studies were reported.
U.S. Pat. No. 3,995,641 presents the novelty of modified cyanoacrylates, namely, carbalkoxyalkyl cyanoacrylates. These also are claimed to be useful for tissue adhesives in surgical applications. The presumed superiority of these products was attributable to the rapid hydrolytic decay and concurrent low degree of histotoxicity. Since no data is presented regarding formaldehyde evolution it is presumed that the hydrolysis mechanism does not scission the polymer to generate it.
U.S. Pat. No. 5,254,132 discloses the use of a hybrid method of surgical application of cyanoacrylates. It claims a combination of sutures and adhesive such as to be mutually isolated from each other, but to both support the re-growth of the tissue in the wound area. It addresses the issue of insuring no contact of adhesive in the suture area so as to assure no inclusions of the cyanoacrylate. This method would appear to be awkward and cumbersome and require a very effective and controlled dispensing of the adhesive without contacting the suture. Additional concern is indicated as a suggestion is made to employ a solvent (acetone) if any surgical instrument happens to be bonded inadvertently to the treated area.
U.S. Pat. No. 5,328,687 attacks the formaldehyde issue by incorporating a formaldehyde scavenger such as sodium bisulfite. The various compositions were evaluated via in-vitro experimentation. The examples presented all had a presumably excessive level of scavenger. The representative compositions had loadings of 20% of a scavenging agent that was designed to offset formaldehyde emissions that were at 0.1%. As indicated previously, in-vitro and in vivo conditions are not identical and certainly not in this instance. The presented in-vitro conditions do not factor in the dynamic conditions in living tissue. The surgically treated area would be under continuous and changing fluids as the organ attempts to bring in the necessary biocomponets to heal the traumatized tissue. As such, it would not be expected that the scavenger/formaldehyde ratio would be maintained as it was in the in-vitro state. It could be speculated that the use of such high loadings of any fluid solubilized additives would contribute to greater formaldehyde emissions. This can be assumed to be a consequence of dissolution of the additives resulting in cavities in the polymer thereby promoting greater surface area for hydrolytic degradation.
U.S. Pat. No. 5,403,591 concerns the use of cyanoacrylates for treatment of skin irritations that progress to ulcerations. It would be assumed that these conditions could be considered wound formations, e.g., see U.S. Pat. No. 3,995,641.
U.S. Pat. Nos. 5,928,611, 5,981,621, 6,099,807, 6,217,603 describe methods of inducing cure of cyanoacrylates by passing the adhesive through a porous applicator tip containing substances that initiate the polymerization.
U.S. Pat. No. 6,143,352 describes methods of altering the pH environment of cyanoacrylates in order to attenuate or accelerate the rate of hydrolytic degradation by uses of acid and alkaline additives. The formulation of acidic modifiers is problematic as they tend to inhibit the primary characteristic of these materials, namely, rapid cure on application to tissue. Data is presented on effects of acidic compositions on previously cured cyanoacrylates.
All of these methods rely on addition of various compositions to effect the accelerated cure onto the desired substrate. These may induce polymerization by creating a greater number of initiation sites and or orientation of the monomer for more facile polymerizations. Other plausible mechanisms can be evoked, but the fact remains that these materials become a part of the composition. As such these chemical inclusions may elicit unfavorable reactions in the cured state. In particular, the use of pH-based accelerators can now contribute to the alkaline hydrolysis of the cyanoacrylate polymer.
This is particularly undesirable in medical applications of the cyanoacrylates as the hydrolysis results in the evolution of formaldehyde. A certain level of formaldehyde can be tolerated by tissue as it is able to dispose of reasonable concentrations. A solution to this was to increase the chain length of the cyanoacrylate monomer side group and in particular that it be alkyl so as to impart hydrophobic character to the resulting polymer.
The current and prior art has been able to achieve a synthesis of the octyl cyanoacrylate at economic levels for applications in the medical field, although improbable for uses in commercial applications due to reaction yields. A number of methods have been attempted to improve yields (12). The variables looked at included: azeotropes, temperature and formaldehyde/cyanoacetate ratio. Other methods have also included assessment of different catalysts for the condensation reaction. Regardless of the methods tried, yields become increasingly smaller as the cyanoacetate pendant group becomes larger.
A reported attempt to improve yields is reported in U.S. Pat. No. 6,245,933. This method attempts to avoid yield losses by producing the high yield cyanoacrylate prepolymers of the lower homologues (methyl & ethyl) and then proceed through a transesterification with a longer chain alcohol such as the octyl. Three reported examples with 2-octanol gave yields ranging from 21.8% to 36.2% of crude monomer.
From this, it can be seen that high yields are difficult and no doubt subsequent workup to medically acceptable products result in even lower product output. The difficulty with methods such as above, is the undesirable side products which are difficult to remove from the main stream. In particular, it is difficult to achieve complete transesterification reactions on polymeric moieties because of steric obstruction. As a consequence, purity is compromised as the initial cyanoacrylate prepolymer is not completely reacted and the lower homologue co-distills with the desired product.
Other additives have been used to attenuate various properties, such as modulus (elasticity), viscosity, thermal resistance, etc. Each and every additive becomes a substance that must be removed by the surrounding tissue, which generally do not assist in recovery of the damaged area. In that regard, the addition of these additives must factor the property improvement against the effect on tissue compatibility.